Periprosthetic joint infections (PJI) can be subcategorized into acute postoperative infections, occurring within three months of implantation, and delayed onset infections, occurring after three months of implantation. PJIs can be caused by numerous infectious etiologies. Here, we describe a unique case of a patient with a history of bilateral shoulder and knee replacements over five years. The patient received a diagnosis of Waldenströms macroglobulinemia five years before her admission but deferred ibrutinib treatment until one year before her admission. We believe that the timeline coincides with the development of multiple PJIs secondary to ibrutinib therapy. The patient presented with bilateral shoulder and knee pain and swelling, following a flu-like illness that had resolved one year before the admission. Her joint symptoms did not subside along with the remaining flu-like symptoms. Initially, her symptoms served as clues to the diagnosis; however, the diagnosis was finally made and supported by joint aspiration. The patient was treated with vancomycin 1.25 g in sodium chloride 0.9% 250 mL intravenous piggyback every 24 hours for the treatment of PJI and oral daptomycin 500 mg daily for six weeks as prophylaxis for PJI. In conclusion, physicians need to consider the development of PJIs when prescribing immunosuppressive therapy, as well as an early diagnosis to prevent further complications.